Heterocyclylindazole and -azaindazole compounds as 5-hydroxytryptamine-6 ligands

ABSTRACT

The present invention provides a compound of formula I and the use thereof in the therapeutic treatment of disorders related to or affected by the 5-HT6 receptor.

This is a divisional of application Ser. No. 10/028,168 filed on Dec.20, 2001, now U.S. Pat. No. 6,767,912, which claims the benefit ofprovisional application Ser. No. 60/257,627 filed on Dec. 22, 2000; theentire disclosure of each application is incorporated by reference.

BACKGROUND OF THE INVENTION

A number of central nervous system disorders such as anxiety,depression, motor disorders, etc., are believed to involve a disturbanceof the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin.Serotonin is localized in the central and peripheral nervous systems andis known to affect many types of conditions including psychiatricdisorders, motor activity, feeding behavior, sexual activity, andneuroendocrine regulation among others. The effects of serotonin areregulated by the various 5-HT receptor subtypes. Known 5-HT receptorsinclude 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.

The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptorsubtype has been cloned, and the extensive distribution of its mRNA hasbeen reported. Highest levels of 5-HT6 receptor mRNA have been observedin the olfactory tubercle, the striatum, nucleus accumbens, dentategyrus and CA1, CA2 and CA3 regions of the hippocampus. Northern blotshave revealed that 5-HT6 receptor mRNA appears to be exclusively presentin the brain, with little evidence for its presence in peripheraltissues.

The high affinity of a number of antipsychotic agents for the 5-HT6receptor, in addition to its mRNA localization in striatum, olfactorytubercle and nucleus accumbens suggests that some of the clinicalactions of these compounds may be mediated through this receptor.Compounds which interact with, stimulate or inhibit the 5-HT6 receptorare commonly referred to as 5-HT6 ligands. These 5-HT6 receptor ligandsare believed to be of potential use in the treatment of a variety ofcentral nervous system disorders such as anxiety, depression, epilepsy,obsessive-compulsive disorders, migraine, cognitive disorders, sleepdisorders, feeding disorders, panic attacks, disorders relating towithdrawl from drug abuse, schizophrenia, or the like or in thetreatment of certain gastrointestinal disorders such as irritable bowelsyndrome.

Therefore, it is an object of this invention to provide compounds whichare useful as therapeutic agents in the treatment of a variety ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment of centralnervous system disorders related to or affected by the 5-HT6 receptor.

It is a feature of this invention that the compounds provided may alsobe used to further study and elucidate the 5-HT6 receptor.

These and other objects and features of the invention will become moreapparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I wherein

-   -   Q is SO₂, CO, CONR₂₄, CSNR₂₅ or CH₂;    -   W is N or CR₆;    -   X is N or CR₇;    -   Y is NR₈ or CR₉R₁₀;    -   n is 0 or an integer of 1 or 2;    -   Z is NR₁₁ or CR₁₂R₁₃ with the proviso that when n is 1, Q is        SO₂, CO or CH₂, and W is CR₆ then Z must be CR₁₂R₁₃ and with the        further provisos that when Y is NR₈ then Z must be CR₁₂R₁₃ and        at least one of Y and Z must be NR₈ or NR₁₁;    -   R₁, R₂ and R₇ are each independently H, halogen, CN, OCO₂R₁₄,        CO₂R₁₅, CONR₂₉R₃₀, CNR₁₆NR₁₇R₁₈, SO_(m)R₁₉, NR₂₀R₂₁, OR₂₂, COR₂₃        or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,        cycloheteroalkyl, aryl or heteroaryl group each optionally        substituted;    -   R₃, R₄, R₉, R₁₀, R₁₂ and R₁₃ are each independently H or an        optionally substituted C₁-C₆alkyl group;    -   R₅ is an optionally substituted C₁-C₆alkyl, aryl or heteroaryl        group;    -   m is 0 or an integer of 1 or 2;    -   R₆ is H, halogen, or an optionally substituted C₁-C₆alkyl,        C₁-C₆alkoxy, aryl or heteroaryl group;    -   R₈ and R₁₁ are each independently H, CNR₂₆NR₂₇R₂₈ or a        C₁-C₆alkyl, C₃-C₆cycloalkyl, cycloheteralkyl, aryl or heteroaryl        group each optionally substituted;    -   R₁₄, R₁₅, R₂₂ and R₂₃ are each independently H or an optionally        substituted C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;    -   R₁₆, R₁₇, R₁₈, R₂₀, R₂₁, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are each        independently H or C₁-C₄alkyl;    -   R₁₉ is an optionally substituted C₁-C₆alkyl, aryl or heteroaryl        group;    -   R₂₄ and R₂ are each independently H or an optionally substituted        C₁-C₆alkyl, aryl or heteroaryl group; and    -   represents a single bond or a double bond; or the stereoisomers        thereof or the pharmaceutically acceptable salts thereof.

The present invention further provides methods and compositions usefulfor the treatment of central nervous system disorders affected by orrelated to the 5-HT6 receptor.

DETAILED DESCRIPTION OF THE INVENTION

The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recentreceptors to be identified by molecular cloning. Its ability to bind awide range of therapeutic compounds used in psychiatry, coupled with itsintriguing distribution in the brain has stimulated significant interestin new compounds which are capable of interacting with or affecting saidreceptor. At present, there are no known fully selective agonists.Significant efforts are being made to understand the possible role ofthe 5-HT6 receptor in psychiatry, cognitive dysfunction, motor functionand control, memory, mood and the like. To that end, compounds whichdemonstrate a binding affinity for the 5-HT6 receptor are earnestlysought both as an aid in the study of the 5-HT6 receptor and aspotential therapeutic agents in the treatment of central nervous systemdisorders.

Surprisingly, it has now been found that heterocyclylindazole or-azaindazole compounds of formula I demonstrate affinity for the 5-HT6receptor along with significant receptor sub-type selectivity.Advantageously, said formula I compounds are effective therapeuticagents for the treatment of central nervous system (CNS) disordersassociated with or affected by the 5-HT6 receptor. Accordingly, thepresent invention provides heterocyclylindazole or -azaindazolecompounds of formula I

wherein

-   -   Q is SO₂, CO, CONR₂₄, CSNR₂₅ or CH₂;    -   W is N or CR₆;    -   X is N or CR₇;    -   Y is NR₈ or CR₉R₁₀;    -   n is 0 or an integer of 1 or 2;    -   Z is NR₁₁ or CR₁₂R₁₃ with the proviso that when n is 1, Q is SO₂        CO or CH₂ and W is CR₆ then Z must be CR₁₂R₁₃ and with the        further provisos that when Y is NR₈ then Z must be CR₁₂R₁₃ and        at least one of Y and Z must be NR₈ or NR₁₁;    -   R₁, R₂ and R₇ are each independently H, halogen, CN, OCO₂ R₁₄,        CO₂R₁₅, CONR₂₉R₃₀, CNR₁₆NR₁₇R₁₈, SO_(m)R₁₉, NR₂₀R₂₁, OR₂₂, COR₂₃        or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,        cycloheteroalkyl, aryl or heteroaryl group each optionally        substituted;    -   R₃, R₄, R₉, R₁₀, R₁₂ and R₁₃ are each independently H or an        optionally substituted C₁-C₆alkyl group;    -   R₅ is an optionally substituted C₁-C₆alkyl, aryl or heteroaryl        group;    -   m is 0 or an integer of 1 or 2;    -   R₆ is H, halogen, or an optionally substituted C₁-C₆alkyl,        C₁-C₆alkoxy, aryl or heteroaryl group;    -   R₈ and R₁₁ are each independently H, CNR₂₆NR₂₇R₂₈ or a        C₁-C₆alkyl, C₃-C₆cycloalkyl, cycloheteralkyl, aryl or heteroaryl        group each optionally substituted;    -   R₁₄, R₁₅, R₂₂ and R₂₃ are each independently H or an optionally        substituted C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;    -   R₁₆, R₁₇, R₁₈, R₂₀, R₂₁, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are each        independently H or C₁-C₄alkyl;    -   R₁₉ is an optionally substituted C₁-C₆alkyl, aryl or heteroaryl        group;    -   R₂₄ and R₂₅ are each independently H or an optionally        substituted C₁-C₆alkyl, aryl or heteroaryl group; and    -   represents a single bond or a double bond; or the stereoisomers        thereof or the pharmaceutically acceptable salts thereof.

As used in the specification and claims, the term halogen designates Br,Cl, I or F; the term aryl designates phenyl or naphthyl; and the termcycloheteroalkyl designates a 5- to 7-membered monocyclic ring systemcontaining 1 or 2 heteroatoms, which may be the same or different,selected from N, O or S and optionally containing one double bond.Exemplary of the cycloheteroalkyl ring systems included in the term asdesignated herein are the following rings wherein Y₁ is NR, O or S and Ris H or an optional substituent as described hereinbelow.

Similarly, as used in the specification and claims, the term heteroaryldesignates a 5- to 10-membered monocyclic or bicyclic aromatic ringsystem containing 1 to 3 heteroatoms, which may be the same ordifferent, selected from N, O or S. Such heteroaryl ring systems includepyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl,quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl,benzisoxazolyl and the like. The term haloalkyl designates aC_(n)H_(2n+1) group having from one to 2n+1 halogen atoms which may bethe same or different; and the term haloalkoxy designates anOC_(n)H_(2n+1) group having from one to 2n+1 halogen atoms which may bethe same or different.

In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynl, C₃-C₇cycloalkyl, cycloheteroalkyl,C₁-C₆alkanoyl, aryl or heteroaryl are designated as being optionallysubstituted, the substituent groups which are optionally present may beone or more of those customarily employed in the development ofpharmaceutical compounds or the modification of such compounds toinfluence their structure/activity, persistence, absorption, stabilityor other beneficial property. Specific examples of such substituentsinclude halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino,formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, cycloheteroalkyl, heteroaryl or cycloalkyl groups, preferablyhalogen atoms or lower alkyl groups. Typically, up to 3 substituents maybe present. When any of the foregoing substituents represents orcontains an alkyl substituent group, this may be linear or branched andmay contain up to 12, preferably up to 6, more preferably up to 4 carbonatoms.

Pharmaceutically acceptable salts may be any acid addition salt formedby a compound of formula I and a pharmaceutically acceptable acid suchas phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,mandelic, malonic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

Compounds of the invention include esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo. Also included are metabolites of thecompounds of the present invention defined as active species producedupon introduction of these compounds into a biological system.

Compounds of the invention may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. One skilled in the art will appreciate that onestereoisomer may be more active or may exhibit beneficial effects whenenriched relative to the other stereoisomer(s) or when separated fromthe other stereoisomer(s). Additionally, the skilled artisan knows howto separate, enrich or selectively prepare said stereoisomers.Accordingly, the present invention comprises compounds of Formula I, thestereoisomers thereof and the pharmaceutically acceptable salts thereof.The compounds of the invention may be present as a mixture ofstereoisomers, individual stereoisomers, or as an optically active form.

Preferred compounds of the invention are those compounds of formula Iwherein n is 1 and Y is NR₈. Also preferred are those compounds offormula I wherein n is 0. Further preferred compounds of the inventionare those compounds of formula I wherein Q is SO₂ or CO and R₅ is anoptionally substituted aryl or heteroaryl group. Another group ofpreferred compounds is those compounds of formula I wherein represents asingle bond.

More preferred compounds of the invention are those compounds of formulaI wherein n is 0; Q is SO₂; X is CR₇; and Z is NR₁₁. Another group ofmore preferred inventive compounds are those formula I compounds whereinn is 1; Q is SO₂; Y is NR₈; X is CR₇; and R₅ is an optionallysubstituted aryl group. Further more preferred compounds of theinvention are those compounds of formula I wherein n is 0; Q is SO₂; Wis CR₆; X is CR₇; Z is NR₁₁; R₅ is an optionally substituted aryl group;and represents a single bond.

Among the preferred compounds of the invention are:

-   1-(phenylsulfonyl)-3-(piperidin-4-yl)-1H-indazole;-   1-(4-nitrophenyl)-3-(piperidin-4-yl)-1H-indazole;-   1-(4-fluorophenyl)-3-(piperidin-4-yl)-1H-indazole;-   1-(4-fluorophenylsulfonyl)-3-(1-methyl-pyrrolidin-3-yl)-1H-indole;-   1-(4-chlorophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-(naphth-2-ylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-(4-aminophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-(3,4-dimethoxyphenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-(3,4-dichlorophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-[(4,5-dichlorothien-2-yl)sulfonyl]-3-(1-methyl-pyrrolidin-3-yl)-1H-indole;-   1-(2-bromophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-(4-iodophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-(2-iodophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;-   1-(4-aminophenylsulfonyl)-3-(1-benzylpyrrolidin-3-yl)-1H-indole;-   3-(1-benzylpyrrolidin-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole;-   3-(1-benzylpyrrolidin-3-yl)-1-(3,4-dichlorophenyl-sulfonyl)-1H-indole;-   3-(1-benzylpyrrolidin-3-yl)-1-(2-bromophenylsulfonyl)-1H-indole;-   5-[3-(1-benzylpyrrolidin-3-yl)-indole-1-sulfonyl]-4-methyl-thiazol-2-ylamine;-   3-(1-benzylpyrrolidin-3-yl)-1-[(5-bromothien-2-yl)sulfonyl]-1H-indole;-   1-phenylsulfonyl-3-(1-methylpyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine;-   1-phenylsulfonyl-3-(1-methylpyrrolidin-3-yl)-1H-indazole;-   1-phenylsulfonyl-3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine;-   1-phenylsulfonyl-3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole;-   1-phenylsulfonyl-3-(1-methylpiperidin-4-yl)-1H-indazole;-   1-phenylsulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole;-   1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;-   1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-indole;-   1-phenylsulfonyl-5-fluoro-3-(1-methylazepan-4-yl)-1H-indole;-   1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;-   1-phenylsulfonyl-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;-   1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-b]pyridine;-   1-phenylsulfonyl-5-fluoro-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;-   1-phenylsulfonyl-5-fluoro-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;-   1-(benzo[b]thioen-4-ylsulfonyl)-3-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine;-   1-(3-fluorophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indazole;-   1-(2,5-dichlorophenylsulfonyl)-3-(2,5-dihydro-1H-pyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine;-   8-[3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)indole-1-sulfonyl]-quinoline;-   1-phenylsulfonyl-5-chloro-3-(1-methylpiperidin-4-yl)-1H-indazole;-   5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-indazole;-   3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-pyrrolo[2,3-b]pyridine;-   3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-indole;-   1-(benzo[b]thien-4-ylsulfonyl)-5-fluoro-3-(1-methylazepan-4-yl)-1H-indole;-   8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;-   3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1ylsulfonyl)-1H-indole;-   8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-pyrrolo[2,3-b]pyridine-1-sulfonyl]-quinoline;-   8-[5-fluoro-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;-   5-fluoro-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1-ylsulfonyl)-1-indole;-   1-(benzo[b]thien-4-ylsulfonyl)-3-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine;-   1-(3-fluoro-phenylsulfonyl)-3-(1-phenethyl-pyrrolidin-3-yl)-1H-indazole;-   1-(2,5-dichlorophenylsulfonyl)-3-(1-ethyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine;-   3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1-(naphth-2-ylsulfonyl)-1H-indole;-   5-chloro-1-(3-fluorophenylsulfonyl)-3-piperidin-4-yl-1H-indazole;-   5-methoxy-1-(naphth-1-ylsulfonyl)-3-(1,2,2-trimethyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indazole;-   1-(naphth-1-ylsulfonyl)-3-(1-phenethyl-azepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;-   3-azepan-4-yl-1-(naphth-1-ylsulfonyl)-1H-indole;-   3-azepan-4-yl-1-(3-chloro-5-methyl-benzo[b]thien-2-ylsulfonyl)-5-fluoro-1H-indole;-   8-[3-(1-phenethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;-   3-[1-(3,3-dimethylbutyl)-2,5,6,7-tetrahydro-1H-azepin-4-yl]-1-(naphth-2-ylsulfonyl)-1H-indole;-   1-(2,3-dichlorophenylsulfonyl)-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-]pyridine;-   1-[(3-chloro-5-methoxyphenylsulfonyl)]-3-(2,2-dimethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-5-fluoro-1H-indole;-   3-azepan-4-yl-5-fluoro-1-(naphth-2-ylsulfonyl)-1H-indole;-   1-benzenesulfonyl-3-piperidin-3-yl-1H-indole;-   1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(4-methoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(4-trifluoromethy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(2-naphthylenesulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;-   1-(2,6-dichloro-imidazo[2,1-b]thiazole-5-sulfonyl)-3-piperidin-3-yl-1H-indole;-   2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-imidazo[1,2-a]pyridine;-   2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;-   1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   1-(2-naphthylenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3b]pyridine;-   1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;-   2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-imidazo[1,2-a]pyridine;-   2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;    -   or the pharmaceutically acceptable salts thereof.

Compounds of the invention may be prepared using conventional syntheticmethods and, if required, standard separation or isolation techniques.For example, compounds of formula I wherein n is 1; Q is SO₂; Y is CH₂;Z is NH; and represents a double bond (Ia) may be prepared by reacting acompound of formula II with a protected 4-piperidone compound of formulaIII, such as 1-t-butoxycarbonyl-4-piperidone, in the presence of a baseto give the protected tetrahydropyridinyl compound of formula IV;sulfonating said formula IV compound to give the protected 1-sulfonylderivative of formula V; and deprotecting the formula V compound to givethe desired formula Ia product. Alternatively, the formula V compoundmay be reduced to give the formula VI protected piperidin-4-ylderivative and deprotection of the formula VI compound affords thecompound of formula I wherein n is 1; Q is SO₂; Y is CH₂, Z is NH; andrepresents a single bond (1b). The reaction schemes are shown in flowdiagram I wherein G represents a protecting group.

Commonly used protecting groups include t-butylcarboxylate, benzyl,acetyl, benzyloxycarbonyl, or any conventional group known to protect abasic nitrogen in standard synthetic procedures.

The corresponding compounds of formula I wherein Z is NR₁₁ and R₁₁ isother than H may be prepared by alkylating the formula Ia or Ib compoundwith an alkylating agent R₁₁-Hal, wherein Hal is Cl, Br or I. Thereaction is illustrated in flow diagram II.

Similarly, commpounds of formula I wherein n is 1; Q is SO₂; Y is NH andZ is CH₂ (Id) may be prepared by reacting a formula II compound with aprotected 3-piperidone of formula VII in the presence of a base to givethe protected tetrahydropyridinyl compound of formula VIII; reducingsaid formula VIII compound via catalytic hydrogenation to give thecompound of formula IX; sulfonating the formula VIII or IX compound togive the corresponding protected 1-sulfonyl derivative and deprotectingsaid derivative to give the desired product of formula Id. The reactionsequence is shown in flow diagram III wherein G represents a protectinggroup.

Compounds of formula I wherein is 0, Q is SO₂; Y is CH₂; Z is NH andrepresents a single bond (Ie) may be prepared by reacting a compound offormula II with a protected maleimide in the presence of an acid to givethe compound of formula X; reducing the formula X compound with LiAlH₄to give the 3-pyrrolidinyl compound of formula XI and sulfonating anddeprotecting as described hereinabove to give the desired product offormula Ie. The reactions are shown in flow diagram IV wherein Grepresents a protecting group.

Utilizing the reactions shown in flow diagrams I, II, and IIIhereinabove and employing the appropriate pyrrolidone or homopiperidoneaffords compounds of formula I wherein n is 0 or 2 and Q is SO₂.Compounds of formula Id or Ie may be alkylated as shown in flow diagramIII to give the corresponding formula I products wherein R₈ or R₁₁ isother than H. Compounds of formula I wherein Q is CO, CONR₂₄ or CH₂ maybe prepared by reacting the protected intermediate of formula IV, VIII,IX or XI with the appropriate carbonyl halide, carbamoyl halide or alkylhalide, respectively. These and other literature procedures may beutilized to prepare the formula I compounds of the invention.

Advantageously, the inventive compound of formula I may be utilized inthe treatment of central nervous system disorders relating to oraffected by the 5-HT6 receptor such as motor, mood, psychiatric,cognitive, neurodegenerative, or the like disorders. In particular, CNSdisorders such as anxiety, depression, schizophrenia, Alzheimer'sdisease, Parkinson's disease, eating disorders, disorders related toalcohol or drug withdrawl, sexual dysfunction, attention deficit, memoryloss or the like. Accordingly, the present invention provides a methodfor the treatment of a disorder of the central nervous system (CNS)related to or affected by the 5-HT6 receptor in a patient in needthereof which comprises providing said patient with a therapeuticallyeffective amount of a compound of formula I as described hereinabove.The compounds may be provided via oral or parenteral administration orin any common manner known to be an effective administration of atherapeutic agent to a patient in need thereof.

The therapeutically effective amount provided in the treatment of aspecific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician andthe like. In general, effective amounts for daily oral administrationmay be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the compounds of the invention are administered in asolid or liquid form, either neat or in combination with one or moreconventional pharmaceutical carriers or excipients. Accordingly, thepresent invention provides a pharmaceutical composition which comprisesa pharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway.

Unless otherwise stated, all parts are parts by weight. The terms HPLCand NMR designate high performance liquid chromatography and nuclearmagnetic resonance, respectively.

EXAMPLE 1 Preparation of 3-(1H-Indol-3-yl)-1-methylpyrrolidine-2,5-dione

A mixture of indole (3.14 g) and N-methylmaleimide (6.2 g, 3 equiv.) inacetic acid is heated at 105° C. for 16 hr, cooled to room temperature,held for 16 hr and filtered. The filtercake is washed with acetic acidand dried to afford the title product, 5.5 g, identified by HPLC andmass spectral analyses.

EXAMPLE 2 Preparation of 3-(1-methylpyrrolidin-3-yl)-1H-indole

A solution of 3-(1-H-indol-3-yl)-1-methyl-pyrrolidine-2,5-dione (1.4 g)in tetrahydrofuran is treated with LiAlH₄ (12 mL, 1.0M solution, 2equiv), stirred at 50° C. for 8 hr, cooled to room temperature, quenchedwith water and 15% aqueous NaOH and filtered. The filtrate is dried overMgSO₄ and concentrated in vacuo to afford the title product as an oil,1.1 g, identified by HPLC and mass spectral analyses.

EXAMPLE 3 Preparation of3-(1-methylpyrrolidin-3-yl)-1-[4-(methylphenyl)sulfonyl]-1H-indole

A solution of 3-(1-methylpyrrolidin-3-yl)-1H-indole (50.1 mg, 0.25 mmol)in tetrahydrofuran is treated sequentially with NaH (60% dispersion inmineral oil, 0.75 mmol) and 4-methylphenylsulfonyl chloride (47 mg, 0.25mmol), stirred for 12 hr and concentrated in vacuo to give a residue.Purification of the residue by HPLC affords the title product as asolid, characterized by HPLC and mass spectral analyses, [M+H] 355.15,LCMS¹ retention time 1.82 min.

-   ¹LCMS conditions: HP1100 MSD system; Waters Xterra C18, 2 mm×50 mm    ID, 5 uM column; 10 uL injectin; Solvent A: 0.02% TFA/water; Solvent    B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.3 min: 95% A; 5    min: 10% A, Flow rate 1 mL/min; Detection: 254 nm DAD.

EXAMPLES 4-27 Preparation of1-(Arylsulfonyl)-3-(N-substituted-pyrrolidin-3-yl)-1H-Indole

Using essentially the same procedures described in Examples 3, 4 and 5and employing the appropriate maleimide and suitable arylsulfonylchloride the compounds shown in Table II are prepared and identified byHPLC and mass spectral analyses. (LCMS¹)

-   ¹LCMS conditions: HP1100 MSD system; Waters Xterra C18, 2 mm×50 mm    ID, 5 uM column; 10 uL injectin; Solvent A: 0.02% TFA/water; Solvent    B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.3 min: 95% A; 5    min: 10% A, Flow rate 1 mL/min; Detection: 254 nm DAD.

TABLE II

Ex. LCMS No. R₈ R5 M + H (min) 4 methyl 4-fluorophenyl 359 1.78 5 methyl4-methoxyphenyl 371 1.82 6 methyl 4-chlorophenyl 375 1.90 7 methyl5-chlorothien-2-yl 381 1.94 8 methyl 2-naphthyl 391 2.05 9 methyl4-anilinyl 356 1.58 10 methyl 3,4-dimethoxyphenyl 401 1.74 11 methyl3,4-dichlorophenyl 409 2.07 12 methyl 4,5-dichlorothien-2-yl 415 2.14 13methyl 2-bromophenyl 419 1.84 14 methyl 2-amino-4-methylthiazol- 3771.53 5-yl 15 methyl 5-chloro-3-methyl-1- 445 2.28 benzothien-2-yl 16methyl 4-iodophenyl 467 1.88 17 methyl 2-iodophenyl 467 2.00 18 benzyl4-methylphenyl 431 2.17 19 benzyl 4-methoxyphenyl 447 2.14 20 benzyl4-aminophenyl 432 1.68 21 benzyl 3,4-dichlorophenyl 487 2.40 22 benzyl2-bromophenyl 495 2.15 23 benzyl 2-amino-4-methylthiazol-5- 453 1.60 yl24 benzyl 5-bromothien-2-yl 501 2.30 26 benzyl 4-iodophenyl 543 2.21 27benzyl 2-iodophenyl 543 2.34

EXAMPLE 28 Preparation of3-(1-Benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-indole

A mixture of indole (2 g, 17 mmol) and 1-benzyl-piperidin-3-onehydrochloride hydrate (7.7 g, 34 mmol) and 2N KOH/isopropanol is heatedat 80° C. for 14 hours, cooled to room temperature, poured overice/water and extracted with ethyl acetate. The extracts are combined,washed with water, dried over Na₂SO₄ and concentrated in vacuo to affordthe title product, identified by HPLC and mass spectral analyses.

EXAMPLE 29 Preparation of 3-Piperidin-3-yl-1H-indole

A mixture of the 3-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indoleobtained in Example 28 and 10% palladium on carbon in a mixture offormic acid and methanol is stirred at room temperature for 3 days andfiltered through celite. The celite is washed with methanol. Thefiltrates are combined and concentrated in vacuo to afford the titleproduct, identified by HPLC and mass spectral analyses.

EXAMPLE 30 Preparation of 3-(1H-Indol-3-yl)-piperidine-1-carboxylic AcidTert-butyl Ester

A solution of the 3-piperidin-3-yl-1H-indole obtained in Example 29 inacetone/water (1:1) at 0° C. is treated with di-tert-dicarbonate (4.1 g,18.7 mmol) and K₂CO₃ (11.75 g, 85 mmol), stirred for 2 hours whilewarming to room temperature, and concentrated in vacuo. The resultantaqueous mixture is extracted with ethyl acetate. The extracts arecombined, dried over Na₂SO₄ and concentrated in vacuo. The resultantresidue is purified by column chromatography (silica gel, 1% NH₄OH inMeOH:CHCl₃, 0:100 to 10:90 as eluent) to afford the title product, 1.25g, identified by HPLC and mass spectral analyses.

EXAMPLE 31 Preparation of 1-Benzenesulfonyl-3-piperidin-3-yl-1H-indole

A solution of 3-(1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butylester (75 mg, 0.25 mmol) and phenylsulfonyl chloride (50 mg, 0.27 mmol)in tetrahydrofuran (THF) at room temperature is treated with potassiumtert-butoxide (0.275 mL, 1 M solution in THF, 0.275 mmol), shaken atroom temperature for 16 hours, treated with HCl (4 N in dioxane, 0.5mL), shaken for 2 hours and concentrated in vacuo to give a residue.Purification of the residue by HPLC¹ affords the title product,characterized by HPLC and mass spectral analyses [M+H] 341.45, LCMS²retention time 1.67 min.

-   ¹HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20    mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02%    TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95%    A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow    rate 22.5 mL/min; Detection: 254 nm DAD.-   ²LCMS conditions: HP1100 MSD system; Waters Xterra C18, 2 mm×50 mm    ID, 5 uM column; 10 uL injectin; Solvent A: 0.02% TFA/water; Solvent    B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.3 min: 95% A; 5    min: 10% A, Flow rate 1 mL/min; Detection: 254 nm DAD.

EXAMPLES 32-57 Preparation of 1-Arylsulfonyl-3-piperidin-3-yl-1H-indole

Using essentially the same procedures described in Examples 28-31 andemploying the appropriate indole or azaindole substrate and a suitablearylsulfonyl chloride the compounds shown in Table III are prepared andidentified by HPLC and mass spectral analyses. (LCMS¹)

-   ¹ LCMS conditions: HP1100 MSD system; Waters Xterra C18, 2 mm×50 mm    ID, 5 uM column; 10 uL injectin; Solvent A: 0.02% TFA/water; Solvent    B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 0.3 min: 95% A; 3    min: 10% A, Flow rate 1 mL/min; Detection: 254 nm DAD.

TABLE III

Ex. LCMS No. R5 X M + H (min) 32 4-isopropylphenyl CH 384 1.95 335-chlorothien-2-yl CH 382 1.83 34 3-chlorophenyl CH 376 1.90 353,4-difluorophenyl CH 377 1.79 36 4-trifluoromethoxyphenyl CH 425 1.9437 4-methoxyphenyl CH 371 1.76 38 4-trifluoromethylphenyl CH 409 1.94 393-chloro-4-methylphenyl CH 390 1.96 40 2-chloro-4-trifluorophenyl CH 4442.02 41 2-naphthyl CH 392 1.94 42 5-chloro-3-methylbenzo[B]- CH 446 2.15thiene-2-yl 43 2,6-dichloro-imidazo[2,1- CH 456 1.90 b]thiazol-5-yl 442-Chloro-imidazo[1,2- CH 416 1.72 a]pyrid-3-yl 452-Chloro-benzo[d]imidazo- CH 472 1.92 [2,1-b]thiazol-3-yl 464-isopropylphenyl N 385 1.95 47 5-chlorothien-2-yl N 383 1.63 483-chlorophenyl N 377 1.65 49 3,4-difluorophenyl N 378 1.62 504-trifluoromethoxyphenyl N 426 1.94 51 4-trifluoromethylphenyl N 4101.86 52 3-chloro-4-methylphenyl N 391 1.84 53 2-chloro-4-trifluorophenylN 445 1.99 54 2-naphthyl N 393 1.82 55 2,6-dichloro-imidazo[2,1- N 4472.13 b]thiazol-5-yl 56 2-Chloro-imidazo[1,2-a]- N 417 1.63 pyrid-3-yl 572-Chloro-benzo[d]- N 473 1.88 imidazo[2,1-b]thiazol-3-yl

EXAMPLE 58 Comparative Evaluation of 5-HT6 Binding Affinity of TestCompounds

The affinity of test compounds for the serotonin 5-HT6 receptor isevaluated in the following manner. Cultured Hela cells expressing humancloned 5-HT6 receptors are harvested and centrifuged at low speed(1,000×g) for 10.0 min to remove the culture media. The harvested cellsare suspended in half volume of fresh physiological phosphate bufferedsaline solution and recentrifuged at the same speed. This operation isrepeated. The collected cells are then homogenized in ten volumes of 50mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at40,000×g for 30.0 min and the precipitate is collected. The obtainedpellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifugedat the same speed. The final pellet is suspended in a small volume ofTris.HCl buffer and the tissue protein content is determined in aliquotsof 10-25 μl volumes. Bovine Serum Albumin is used as the standard in theprotein determination according to the method described in Lowry et al.,J. Biol. Chem., 193:265 (1951). The volume of the suspended cellmembranes is adjusted to give a tissue protein concentration of 1.0mg/ml of suspension. The prepared membrane suspension (10 timesconcentrated) is aliquoted in 1.0 ml volumes and stored at −70° C. untilused in subsequent binding experiments.

Binding experiments are performed in a 96 well microtiter plate format,in a total volume of 200 μl. To each well is added the followingmixture: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer (pH7.4) containing 10.0 mM MgCl₂ and 0.5 mM EDTA and 20 μl of [³H]-LSD(S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. Thedissociation constant, K_(D) of the [³H]LSD at the human serotonin 5-HT6receptor is 2.9 nM, as determined by saturation binding with increasingconcentrations of [³H]LSD. The reaction is initiated by the finaladdition of 100.0 μl of tissue suspension. Nonspecific binding ismeasured in the presence of 10.0 μM methiothepin. The test compounds areadded in 20.0 μl volume.

The reaction is allowed to proceed in the dark for 120 min at roomtemperature, at which time, the bound ligand-receptor complex isfiltered off on a 96 well unifilter with a Packard Filtermate® 196Harvester. The bound complex caught on the filter disk is allowed to airdry and the radioactivity is measured in a Packard TopCount® equippedwith six photomultiplier detectors, after the addition of 40.0 μlMicroscint®-20 scintillant to each shallow well. The unifilter plate isheat-sealed and counted in a PackardTopCount® with a tritium efficiencyof 31.0%.

Specific binding to the 5-HT6 receptor is defined as the totalradioactivity bound less the amount bound in the presence of 10.0 μMunlabeled methiothepin. Binding in the presence of varyingconcentrations of test compound is expressed as a percentage of specificbinding in the absence of test compound. The results are plotted as log% bound versus log concentration of test compound. Nonlinear regressionanalysis of data points with a computer assisted program Prism® yieldedboth the IC₅₀ and the K_(i) values of test compounds with 95% confidencelimits. A linear regression line of data points is plotted, from whichthe IC₅₀ value is determined and the K_(i) value is determined basedupon the following equation:K _(i) =IC ₅₀/(1+L/K _(D))where L is the concentration of the radioactive ligand used and K_(D) isthe dissociation constant of the ligand for the receptor, both expressedin nM.

Using this assay, the following Ki values are determined and compared tothose values obtained by representative compounds known to demonstratebinding to the 5-HT6 receptor. The data are shown in Table IV, below.

TABLE IV Test Compound 5-HT6 Binding Ki (Ex. No.) (nM) 4 2 6 1 8 3 9 110 5 11 3 12 4 13 1 16 1 17 2 18 8 20 1 21 15 22 14 23 3 24 9 31 2 32 533 3 34 2 35 7 37 10 38 10 39 6 41 8 47 7 48 6 Clozapine 6.0 Loxapine41.4 Methiothepin 8.3 Bromocriptine 23.0 Mianserin 44.2 Olzanzepine 19.5

As can be seen from the data in table II, the compounds of the inventiondemonstrate a high affinity for the 5-HT6 receptor.

1. A compound of formula I

wherein Q is SO₂; either W is N or CR₆ and X is N, or W is CR₆ and X isN or CR₇; Y is NR₈ or CR₉R₁₀; n is an integer of 1; Z is NR₁₁ or CR₁₂R₁₃with the proviso that when W is CR₆ then Z must be CR₁₂R₁₃ and with thefurther provisos that when Y is NR₈ then Z must be CR₁₂R₁₃ and at leastone of Y and Z must be NR₈ or NR₁₁; R₁, R₂ and R₇, are eachindependently H, halogen, CN, OCO₂R₁₄, CO₂R₁₅, CONR₂₉R₃₀, CNR₁₆NR₁₇R₁₈,SO_(m)R₁₉, NR₂₀R₂₁, OR₂₂, COR₂₃ or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted; R₃, R₄, R₉, R₁₀, R₁₂ and R₁₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group; R₅ is anoptionally substituted C₁-C₆alkyl, aryl or heteroaryl group; m is 0 oran integer of 1 or 2; R₆ is H, halogen, or an optionally substitutedC₁-C₆alkyl, C₁-C₆alkoxy, aryl or heteroaryl group; R₈ and R₁₁ are eachindependently H, CNR₂₆NR₂₇R₂₈ or a C₁-C₆alkyl, C₃-C₆cycloalkyl,cycloheteralkyl, aryl or heteroaryl group; R₁₄, R₁₅, R₂₂ and R₂₃ areeach independently H or an optionally substituted C₁₋C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group; R₁₆, R₁₇, R₁₈, R₂₀, R₂₁, R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀are each independently H or C₁-C₄alkyl; R₁₉, is an optionallysubstituted C₁-C₄alkyl, aryl or heteroaryl group; R₂₄ and R₂₅ are eachindependently H or an optionally substituted C₁-C₆alkyl, aryl orheteroaryl group; and represents a single bond or a double bond; or thestereoisomers thereof or the pharmaceutically acceptable salts thereof.2. The compound according to claim 1 wherein Y is NR₈.
 3. The compoundaccording to claim 1 wherein W is N.
 4. The compound according to claim3 wherein Z is NR₁₁.
 5. The compound according to claim 1 wherein Q isSO₂ and R₅ is an optionally substituted aryl or heteroaryl group.
 6. Thecompound according to claim 5 wherein X is CH and represents a singlebond.
 7. The compound according to claim 1 selected from the groupconsisting of: 1-benzenesulfonyl-3-piperidin-3-yl-1H-indole;1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(4-methoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(4-trifluoromethy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(2-naphthylenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;1-(2,6-dichloro-imidazo[2,1-b]thiazole-5-sulfonyl)-3-piperidin-3-yl-1H-indole.2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-imidazo[1,2-a]pyridine;2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(2-naphthylenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-imidazo[1,2-a]pyridine;2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;and the pharmaceutically acceptable salts thereof.
 8. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier and aneffective amount of a compound of formula I

wherein Q is SO₂; either W is N or CR₆ and X is N, or W is Cr₆ and X isN or CR₇; Y is NR₈, or CR₉R₁₀; n is an integer of 1; Z is NR₁₁ orCR₁₂R₁₃ with the proviso that when W is CR₆ then Z must be CR₁₂R₁₃ andwith the further provisos that when Y is NR₈ then Z must be CR₁₂R₁₃ andat least one of Y and Z must be NR₈ or NR₁₁; R₁, R₂ and R₇ are eachindependently H, halogen, CN, OCO₂R₁₄, CO₂R₁₅, CONR₂₉R₃₀, CNR₁₆NR₁₇R₁₈,SO_(m)R₁₉, NR₂₀R₂₁, OR₂₂, COR₂₃ or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroarylgroup each optionally substituted; R₃, R₄, R₉, R₁₀, R₁₂ and R₁₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group; R₅ is anoptionally substituted C₁-C₆alkyl, aryl or heteroaryl group; m is 0 oran integer of 1 or 2; R₆is H, halogen, or an optionally substitutedC₁-C₆alkyl, C₁-C₆alkoxy, aryl or heteroaryl group; R₈ and R₁₁ are eachindependently H, CNR₂₆NR₂₇R₂₈ or a C₁-C₆alkyl, C₃-C₆cycloalkyl,cycloheteralkyl, aryl or heteroaryl group; R₁₄, R₁₅, R₂₂ and R₂₃ areeach independently H or an optionally substituted C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group; R₁₆, R₁₇, R₁₈, R₂₀, R₂₁, R₂₆, R₂₇, R₂₈, R₂₉, and R₃₀are each independently H or C₁-C₄alkyl; R₁₉ is an optionally substitutedC₁-C₆alkyl, aryl or heteroaryl group; R₂₄ and R₂₅ are each independentlyH or an optionally substituted C₁-C₆alkyl, aryl or heteroaryl group; andrepresents a single bond or a double bond; or the stereoisomers thereofor the pharmaceutically acceptable salts thereof.
 9. The compositionaccording to claim 8 having a formula I compound wherein n is 1; Q isSO₂; Y is NR₈; and X is CR₇.
 10. The composition according to claim 8having a formula I compound wherein Q is SO₂; X is CR₇; and Z is NR₁₁.11. The composition according to claim 9 having a formula I compoundwherein R₅ is an optionally substituted aryl group and represents asingle bond.
 12. The composition according to claim 8 having a formula Icompound selected from the group consisting of:1-benzenesulfonyl-3-piperidin-3-yl-1H-indole;1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(4-methoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(4-trifluoromethy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(2-naphthylenesulfonyl)-3-piperidin-3-yl-1H-indole;1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;1-(2,6-dichloro-imidazo[2,1-b]thiazole-5-sulfonyl)-3-piperidin-3-yl-1H-indole;2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-imidazo[1,2-a]pyridine;2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(2-naphthylenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-imidazo[1,2-a]pyridine;2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;and the pharmaceutically acceptable salts thereof.
 13. A process for thepreparation of a compound of formula If

wherein Q is SO₂; W is N or CR₆; either W is N or CR₆ and X is N, or Wis CR₆ and X is N or CR₇; Y is NR₈ or CR₉R₁₀; n is an integer of 1; Z isNR₁₁ or CR₁₂R₁₃ with the proviso that when W is CR₆ then Z must beCR₁₂R₁₃ and with the further provisos that when Y is NR₈ then Z must beCR₁₂R₁₃ and at least one of Y and Z must be NR₈ or NR₁₁; R₁, R₂ and R₇are each independently H, halogen, CN, OCO₂R₁₄, CO₂R₁₅, CONR₂₉R₃₀,CNR₁₆NR₁₇R₁₈, SO_(m)R₁₉, NR₂₀R₂₁, OR₂₂, COR₂₃ or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group each optionally substituted; R₃, R₄, R₉, R₁₀, R₁₂ andR₁₃ are each independently H or an optionally substituted C₁-C₆alkylgroup; R₅ is an optionally substituted C₁-C₆alkyl, aryl or heteroarylgroup; m is 0 or an integer of 1 or 2; R₆ is H, halogen, or anoptionally substituted C₁-C₆alkyl, C₁-C₆alkoxy, aryl or heteroarylgroup; R₈, and R₁₁ are each independently H, CNR₂₆NR₂₇R₂₈ or aC₁-C₆alkyl, C₃-C₆cycloalkyl, cycloheteralkyl, aryl or heteroaryl group;R₁₄, R₁₅, R₂₂ and R₂₃ are each independently H or an optionallysubstituted C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl or heteroaryl group; R₁₆, R₁₇, R₁₈, R₂₀, R₂₁,R₂₆, R₂₇, R₂₈, R₂₉ and R₃₀ are each independently H or C₁-C₆alkyl; R₁₉is an optionally substituted C₁-C₆alkyl, aryl or heteroaryl group; R₂₄and R₂₅ are each independently H or an optionally substitutedC₁-C₆alkyl, aryl or heteroaryl group; and represents a single bond or adouble bond which process comprises reacting a compound of formula IVa

wherein W, X, Y, Z, n, R₁, R₂, R₃ and R₄ are as defined above with asulfonyl chloride, R₅SO₂Cl, wherein R₅ is defined above in the presenceof a base.